EP0694167B1 - An integrated packaging-holder device for immunochromatographic assays in flow-through or dipstick formats - Google Patents

An integrated packaging-holder device for immunochromatographic assays in flow-through or dipstick formats Download PDF

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Publication number
EP0694167B1
EP0694167B1 EP94914781A EP94914781A EP0694167B1 EP 0694167 B1 EP0694167 B1 EP 0694167B1 EP 94914781 A EP94914781 A EP 94914781A EP 94914781 A EP94914781 A EP 94914781A EP 0694167 B1 EP0694167 B1 EP 0694167B1
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EP
European Patent Office
Prior art keywords
assay
sample
analyte
laminate
detection zone
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EP94914781A
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German (de)
English (en)
French (fr)
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EP0694167A1 (en
Inventor
F. Victor Lee-Own
Judith Fitzpatrick
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Serex Inc
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Serex Inc
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54386—Analytical elements
    • G01N33/54387—Immunochromatographic test strips
    • G01N33/54388—Immunochromatographic test strips based on lateral flow
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/558—Immunoassay; Biospecific binding assay; Materials therefor using diffusion or migration of antigen or antibody
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54386—Analytical elements
    • G01N33/54387—Immunochromatographic test strips
    • G01N33/54391—Immunochromatographic test strips based on vertical flow
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/97—Test strip or test slide

Definitions

  • the present invention relates to assay devices for detecting the presence of analyte in a sample.
  • the assay can be performed in a single apparatus for use in a laboratory or a field setting.
  • Immunochromatographic assays using a membrane as a solid support in a dipstick or flow-through device are now established for use in the clinical laboratory and for alternative, i . e ., non-laboratory, site testing. Assays using this type of format are available for drugs of abuse (cocaine, cannabinoid, amphetamines, opiates, PCP), pregnancy and fertility (hCG and hLH, respectively), and infectious diseases (chlamydia, Strep A, infectious mononucleosis (IM)).
  • an immunochromato-graphic assay device is a membrane (cellulosic or non-cellulosic) enclosed in a plastic holder. This device is further packaged singly or in bulk in a sealed foil or plastic pouch, which acts as an environmental control. Package integrity is essential for extended stability of the device at room temperature.
  • the plastic holder keeps the membrane in a suitable configuration in order to ensure correct functioning of the entire device.
  • the test window may also allow for viewing of a control reaction, e . g ., to confirm adequate performance of the test; alternatively, the control window may be separate from the result or test window.
  • the plastic holder also usually holds the membrane in contact with pads (cellulosic or non-cellulosic) which serve as wicks.
  • the plastic device containing the membrane and pads is usually packaged in a sealed foil or plastic pouch with or without desiccant.
  • the outer packaging pouch is essential as an environmental control, particularly to limit exposure of the membrane strip to the external environment and to ensure integrity of the test. Low humidity within the package is important or essential for extended room temperature stability of the device, thus a desiccant is usually present.
  • test procedure involves opening the outer packaging and removal of the plastic device, application of the sample at the sample window (by dipping the device into the sample, or by dropping the sample onto the sample window), waiting the recommended time for running the assay, and checking the result window for a positive or negative result and the control window to determine whether the test proceeded correctly.
  • test devices present certain drawbacks. For example, if the devices are packaged in bulk, any breach of the packaging, whether by an accidental tear or to retrieve a device for a test, will limit the shelf life of the devices. Individual packaging of each test device is expensive, and produces additional solid waste for disposal.
  • the labeled reagent migrates to a trap, which is membrane coated with either receptor (if the labeled reagent is analyte) or analyte (if the labeled reagent is receptor). If the sample contains analyte it binds to the receptor (either mobile or stationary phase) and the marker is not captured by the trap, yielding a "negative" signal. If the sample does not contain the analyte, the marker is captured by the trap and a spot appears, i.e. a "positive" signal. So in a standard competitive assay a negative result has a positive signal.
  • GB-A-2,204,398 discloses an assay device for use in the immunological detection of one or more analytes in a sample.
  • the device has a moisture-impervious, moulded or fabricated, hollow housing construction containing a dry porous carrier.
  • the carrier has one zone for labelling the analyte and a zone for detecting the labelled analyte after migration across the carrier; the detection zone being located for visibility beneath a window through the housing material.
  • a portion of the porous carrier communicates directly or indirectly, with the exterior of the housing, via a bibulous sample collector, for reception of a sample to be analysed.
  • EP-B-0,383,619 is in many respects closely similar to the disclosure of GB-A-2,204,398.
  • EP-B-0,383,619 discloses a quantitative assay device wherein a labelled reagent is contained in a dry state in a macroporous body, which is interposed between a bibulous sample collector and the porous assay carrier. Incorporation of the reagent in the macroporous body avoids the need to apply the labelled reagent to a special zone in the carrier.
  • the present invention is directed at assay methods as defined in appended claims 22 to 24.
  • the present invention relates to an integrated packaging-holder laminate for flow-through and dipstick immunochromatographic assays.
  • the device comprises means for conducting an immunochromato-graphic assay, e . g ., a membrane onto which the assay reagents have been previously impregnated, totally surrounded by means for sealing the immunochromatographic assay means in a substantially air-tight and a substantially fluid-tight manner, e.g. , Mylar RTM , plastic or other suitable support.
  • the sealing means contact and support the assay means, and are adapted to be opened to expose the assay means.
  • the laminate can be sealed with double sided tape or adhesive film, or any other method such as sonic welding, that will similarly enclose the membrane strip in an air-tight and fluid-tight manner.
  • the laminate thus acts as an integral holder for the membrane as well as a packaging pouch. Configurations include a single strip or multiple strips in one laminate, and a single strip may have capability of running multiple tests simultaneously.
  • the invention preferably comprises a test-strip membrane enclosed totally by direct contact on all surfaces with the laminating adhesive supplied as double sided tape or adhesive film.
  • the strip is then given support as needed by overlaying with plastic, Mylar RTM , or other suitable material on the back (non-viewing) side.
  • the front (viewing side) can be covered with transparent plastic.
  • a further layer of opaque material (white or colored plastic, tape, card, paper, paint, pigment, etc.) is then attached directly over the transparent plastic (front) by adhesive, leaving suitable window(s) for viewing results.
  • the laminate contains the totally enclosed test-strip membrane, which is thus presented in its own dedicated holder/packaging pouch, isolated from the external atmosphere. This eliminates the need for separate packaging (plastic/foil pouch or blister pack) for the device.
  • the invention may be used with any assay format that is compatible with an immunochromatographic assay, e . g ., “competitive” and “sandwich” assays.
  • the immunochromatographic assay device of the invention provides its own packaging material.
  • the assay device does not require extraneous wicks or pads to augment sample migration, nor are extra fluids required for sample migration.
  • the invention is based on the surprising discovery that an immunochromatographic assay support, such as a nylon strip, that has been sealed in an air-tight and fluid-tight manner, can be used in an immunochromatographic assay.
  • the present invention further relates to a zone for positively detecting the presence of an analyte in a sample in a competitive immunochromatographic assay on an assay strip.
  • the immunochromatographic assay includes a mobilizable labeled reagent, such that in the presence of a liquid sample the labeled reagent is transported with the sample along the assay strip to a detection zone.
  • the detection zone contains label immobilized in an area of the detection zone such that there is a contrast between the label and the membrane strip in the detection zone.
  • a contrasting signal in the detection zone indicates the presence of analyte in the sample and a non-contrasting signal in the detection zone indicates the absence of analyte in the sample.
  • FIG. 1 is a top view of a device of the present invention.
  • Fig. 2 is a cross-section end view of the device in FIG. 1.
  • FIG. 3 is a cross section side view of the device in FIG. 1.
  • FIG. 4 is a top view of another embodiment of a device of the present invention.
  • FIG. 5 is a side view of yet another embodiment of the device of the present invention.
  • FIG. 6 is a top view of a schematic of a partial construction of a specific embodiment of the invention.
  • FIG. 7 is a cutaway end view of the device shown in FIG. 6.
  • FIG. 8 is a top view of the completed device shown in FIG. 6.
  • FIG. 9 is a cutaway end view of the device shown in FIG. 8.
  • FIG. 10 is a top view of specific embodiment of another device of the invention.
  • FIG. 11 is a cutaway end view of the device shown in FIG. 10.
  • the present invention relates to an immunochromatographic assay device (FIGS. 1, 2 and 3) for detecting the presence of an analyte in a sample.
  • the assay device comprises means for conducting an immunochromatographic assay 12 in contact with and sealed within a substantially air-tight and substantially fluidtight means for sealing (18a and 18b).
  • the invention further comprises a support means 20, which supports the sealing means.
  • the sealing means contact and support the assay means.
  • the sealing means are adapted to be opened by the user to provide access to the assay means, i.e., to apply sample.
  • the invention further provides a detection system that gives a positive result in a competitive immunoassay format when an analyte of interest is present in a sample.
  • sample refers to an aqueous liquid sample suspected of containing an analyte of interest.
  • samples include but are not limited to blood, plasma, serum, urine, saliva, sweat, effusions, fluid, and materials reconstituted or dissolved in a suitable aqueous solvent, e.g. , a buffer solution.
  • analyte refers to a molecule of interest.
  • Analytes may be any antigen, but small analytes (MW of 100 to 1000 Daltons) are of primary interest. Such analytes include therapeutic drugs and metabolites thereof, illicit drugs and metabolites thereof, steroids, and peptide hormones. Nevertheless, assays may be for larger molecules such as protein hormones, e.g., insulin, or viral antigens, bacterial antigens, serum proteins, antibodies or any antigen of interest where detection of the presence (or absence) of the analyte in a rapid, specific, sensitive assay is desirable.
  • protein hormones e.g., insulin, or viral antigens, bacterial antigens, serum proteins, antibodies or any antigen of interest where detection of the presence (or absence) of the analyte in a rapid, specific, sensitive assay is desirable.
  • the device of the invention comprises means for conducting an immunochromatographic assay ("immunochromatographic assay means").
  • immunochromatographic assay means Many immunochromatographic assay means and formats are known in the art (see Section 2.1, supra), and can be used in the practice of the present invention.
  • an immunochromatographic assay involves use of a solid phase support for conducting a liquid.
  • solid phase means for conducting a liquid refers to a solid support that allows migration of a liquid therethrough, e.g. , via capillary action.
  • the solid phase support should behave as a hydrogel.
  • hydrogel materials permit the migration of a liquid sample into the substantially air-tight environment of the device of the invention.
  • a suitable solid phase immunochromato-graphic assay means is a nylon membrane, which is the preferred solid phase support for this purpose, although any solid phase which permits movement of the sample may be used.
  • Other suitable solid phase supports for include, but are not limited to, coated plastic and coated glass, e.g., such as is used for thin layer chromatography, filters, polymer beads, silica gel, paper, membranes, agarose gel, polyacrylamide gel, gelatin, etc.
  • the solid phase support may be impregnated with hydrogel materials such as, but not limited to, proteins (e . g ., collagen, gelatin, albumin, etc.), polyethylene glycol, charged or neutral polysaccharides (e.g. , hyaluronic acid, xanthates, alginates, guar gum, agarose, etc.) and starches.
  • hydrogel materials such as, but not limited to, proteins (e . g ., collagen, gelatin, albumin, etc.), polyethylene glycol, charged or neutral polysaccharides (e.g. , hyaluronic acid, xanthates, alginates, guar gum, agarose, etc.) and starches.
  • adhesive polymers used to seal the immunochromato-graphic assay means can also have hydrogel properties.
  • the immunochromatographic assay means of the invention will preferably be a membrane strip, more preferably a nylon membrane strip. However, it is contemplated that the immunochromatographic means may be formatted for radial migration of liquid sample, e.g. , as on a disk.
  • the present invention can be used with any assay format adaptable to an immunochromatographic assay.
  • the immunochromatographic assay means will contain a mobilizable labeled reagent and a detection zone for detecting the labeled reagent.
  • labeled reagent refers to labeled receptor specific for the analyte of interest, or labeled analyte
  • mobility means that the reagent will move along the solid phase support with the liquid sample.
  • the mobilizable labeled reagent is located on the solid phase support so that it can be mobilized by the liquid sample and moved to the detection zone.
  • the labeled reagent is labeled analyte.
  • the detection zone contains a specific binding partner of the labeled reagent immobilized in the detection zone, i . e ., analyte if labeled receptor is used, or receptor if labeled analyte is used (see Section 2.2, supra ). As pointed out in Section 2.2, supra , there is an inverse correlation between detection of label in the detection zone and the presence of analyte in the sample.
  • one receptor is labeled, and another receptor, which does not compete with the first receptor for binding to analyte, is immobilized in the detection zone.
  • analyte When analyte is present, it will bind both labeled receptor and immobilized receptor, thus localizing the label in the detection zone. In this case, a signal directly correlates with the presence of analyte.
  • the immunochromatographic assay means includes a control to indicate that the assay has proceeded correctly.
  • the control can be a specific binding spot more distal from the sample application point on the solid phase support than the detection zone that will bind to labeled reagent in the presence or absence of analyte, thus indicating that the mobilizable receptor has migrated a sufficient distance with the liquid sample to give a meaningful result.
  • receptor refers to a molecule that can specifically bind to analyte.
  • Suitable receptors for use in assays of the invention include antibodies, cell surface receptors (or a fragment of a cell surface receptor that contains the binding site of analyte and ligand), enzymes (or the substrate binding site of an enzyme), or any other molecule or macromolecule capable of specifically binding to and forming a complex with a ligand and complex with an analyte.
  • Antibodies and cell surface receptors are preferred, with antibodies more preferred.
  • receptor is generated or selected to be specific for the most unique epitope on the analyte.
  • Suitable labels include enzymes, fluorophores, chromophores, radioisotopes, dyes, colloidal gold, latex particles, and chemiluminescent agents.
  • a control marker When a control marker is employed, the same or different labels may be used for the receptor and control marker.
  • the label In a specific embodiment, infra , the label is a colored latex particle.
  • the device also comprises a means for sealing the immunochromatographic assay means ("sealing means"), also referred to as a sealing member.
  • sealing means refer to a material that can be used to seal the immunochromatographic assay means in a substantially air-tight and a substantially liquid-tight manner.
  • the sealing means should also be substantially non-wettable, i . e ., it does not absorb significant amounts of water.
  • material useful as sealing means includes, but is not limited to, adhesive tape, plastic, Mylar RTM and the like.
  • the sealing means are sealed with an adhesive.
  • the sealing means are sealed with a sonic weld.
  • sealing with an adhesive confers non-rigidity to the device, allowing migration of air into interstitial spaces of the adhesive or slight separation of the sealing means to allow for the movement of liquid in the solid phase support.
  • the device also comprises a means for supporting the device (“support means"), also referred to as a support member.
  • support means also referred to as a support member.
  • support means refer to a material which can act to reinforce the solid phase means for conducting a liquid, i.e. , to buttress or brace a membrane strip.
  • the support means is selected from a material that can be attached to the sealing means, e.g. , via an adhesive.
  • the support means can also act as sealing means.
  • Materials for use as support means include, but are not limited to, glass, plastic, Mylar RTM and the like.
  • the support means is transparent plastic that is stiff enough to support a nylon membrane.
  • a relatively non-stiff material can have suitable stiffeners attached thereto.
  • the solid phase means for conducting a liquid is laminated between the sealing means and the support means.
  • the dimensions of both the support means and the sealing means are larger that the dimensions of the immunochromatographic assay means.
  • the device defines a transparent window aligned with the test zone for viewing the assay results.
  • the invention further contemplates sealing more than one immunochromatographic assay means, e.g. , membrane strips, in a single device, to allow for multiple assays.
  • immunochromatographic assay means e.g. , membrane strips
  • a membrane strip 12 onto which the assay reagents have been previously impregnated and stabilized, is attached directly to a sealing member 10 (plastic, Mylar RTM or other suitable material) by means of any lamination technique such as double sided tape or adhesive film 18a , or sonic welding.
  • a further application of double sided tape or adhesive film 18b is then applied to the remaining exposed membrane surface, followed by a layer of stiff transparent plastic sheet 20 to totally enclose the membrane strip.
  • the stiff transparent plastic sheet 20 can be sealed to the sealing member 10 by sonic welding.
  • the transparent plastic sheet 20 can then be overlaid indirectly with double sided tape or adhesive film 18c followed by white or colored tape or plastic 22 (or alternatively directly with white or colored adhesive backed tape or plastic 22 ) leaving an appropriate window 14 (or windows) to allow for viewing of the test result and control reaction.
  • the transparent plastic sheet 20 can be painted, stained, or colored to define a window 14 .
  • the membrane strip is totally enclosed within non-wettable sheets in packaging which serves the duplicate function of membrane holder and moisture barrier pouch.
  • the assay is carried out simply by exposing the end of the membrane strip, e.g. , by cutting the laminate or by peeling off a protective cover. Preferably, cut marks 16 are indicated on the device. This exposed membrane is then dipped into the sample (which enters through the exposed end) and migrates up the membrane. Alternatively the device can just be immersed in the sample (for example, a full urine collection vessel) and the sample will enter through the exposed end of the membrane (the only channel of access available) and migrate up. In another embodiment, the sample can be applied to the exposed membrane. The result is read as the presence or absence of label in the detection zone. In a preferred aspect, the label is observed through the viewing window 14 . Moreover, because the device is an integral arrangement of the immunochromatographic assay totally enclosed in the packaging, it can be removed from the sample, dried off, preferably resealed ( e.g. , with adhesive tape) and stored conveniently as a permanent record.
  • Selection of membrane and lamination method can be controlled so that such devices have controlled pore sizes and effectively eliminate particles above a certain size, such as red-blood cells, making such a device useful for whole blood.
  • the device of the present invention provides for enclosing any immunochromatographic assay means, e.g. , a membrane strip, such as used in immunochromato-graphic assays in dipstick or flow-through format for pregnancy (hCG), fertility (hLH), infectious mononucleosis (IN), Strep A, chlamydia, and drugs of abuse, using lamination so that the membrane is contacted on all sides and totally enclosed.
  • the laminate can be then be completed with plastic, Mylar RTM or any other material as required for rigidity and or cosmetic appearance.
  • the membrane is thus held in a device that acts as an integral holder and packaging pouch.
  • a membrane such as that described in U.S. Patent Application Serial No. 07/737,091, filed July 29, 1991 and corresponding WO-A- 9303175 can be used in the device.
  • the device of the present invention provides good control of liquid sample migration, since the volume of sample entering the device is limited by the physical dimensions of the enclosed test-strip membrane.
  • the migration of the sample is strictly controlled by the physical limitations imposed by the confinement of the test-strip membrane in the laminate.
  • the volume of sample that enters is controlled by the area of membrane used.
  • the laminate is assembled from test-strip membranes and sheets of materials (adhesive films, tapes, transparent plastic sheets, etc.) then the final laminate is die-cut at the required dimensions. This eliminates the cost involved in using precut or molded components and the accuracy that would be involved in the assembly of individual components into a laminate.
  • a colored indicator strip 26 that can indicate the presence of moisture levels (blue for low humidity, pink for high humidity), is incorporated into the device.
  • Suitable indicator strips are sold by Multiform Desiccants.
  • a suitable moisture indicator can be impregnated in a part of the solid phase support that is not intended to contact a sample.
  • the colored area is given its own viewing window at the top or bottom of the laminate. The indicator serves as a confirmation of package integrity. When the colored area is pink --indicating high moisture -- the laminate integrity has been compromised and the test device should not be used. Satisfactory package integrity is indicated by the colored area remaining blue.
  • the laminate is incorporated into a sample collection vessel 30, such as a urine collection vessel, thus allowing immediate specimen testing in the collection container.
  • the collection vessel should be transparent to allow for viewing of the result.
  • the device is attached to the inside wall of the collection vessel by adhesive film, double sided tape, or a sonic weld.
  • the laminate can be precut, with the test-strip membrane exposed ( i . e ., as if the test is ready to run).
  • the collection vessel is then sealed (cap 32 screwed on, etc.) to provide the package integrity.
  • the device may include a removable adhesive strip so that the membrane strip remains sealed within the laminate until the test is ready to run. In this case, the adhesive strip is removed prior to adding the sample.
  • the test runs automatically when the sample is collected in the vessel. The amount of sample collected need only be sufficient to be above the level at which the test-strip membrane is exposed.
  • the present invention provides an advantageous detection zone for a competitive assay format.
  • the detection zone of the invention gives a positive signal when analyte is present in the sample, and a negative signal when analyte is not present in the sample, in contrast to standard competitive assay techniques (see Section 2.2, supra).
  • the immunochromatographic assay includes a mobilizable labeled reagent, such that in the presence of a liquid sample the labeled reagent is transported with the sample along the assay strip to a detection zone.
  • the label has been immobilized in part, but not all, of the detection zone such that there is a contrast between the label and the membrane strip in the detection zone.
  • the detection zone also includes a specific binding partner of the labeled reagent, as described above.
  • labeled reagent binds to the specific binding partner in the detection zone, i . e ., in the absence of analyte in the sample
  • the contrast between the label in the detection zone and the membrane strip is lost.
  • the labeled reagent does not bind to the detection zone, i . e ., in the presence of analyte
  • the contrasting signal remains.
  • a contrasting signal in the detection zone indicates the presence of analyte in the sample and a non-contrasting signal in the detection zone indicates the absence of analyte in the sample. In this way, the signal directly correlates with the presence of analyte in the sample.
  • the detection zone contains a specific binding partner of the labeled reagent in one section, and a non-specific, i.e. , control, binding partner of the labeled reagent (or alternatively a binding partner of a control labeled reagent) in another part.
  • the control reagent will bind in the control area of the detection zone, while the labeled reagent will not, thus producing a contrast between labeled and unlabeled areas of the detection zone, indicating (1) a "positive” result and (2) that the assay ran correctly.
  • the entire detection zone will be labeled, indicating (1) a "negative” result and (2) that the assay ran correctly. If the detection zone is not labeled at all, the assay failed to run.
  • the contrasting areas in the detection zone can be arranged in shapes, such as "+" signs or letters.
  • any label system commonly used for immunochromatographic assays can be used according to the present invention.
  • Rabbit antibody to cotinine Rabbit antibody raised against a cotinine derivative were prepared against a trans-4-hydroxycotinine-KLH conjugate using standard procedures, as described in U.S. application serial no. 07/737,526, filed July 29, 1991 and International Patent Publication No. WO 93/03367, published February 18, 1993.
  • the antibody was affinity purified batchwise by affinity chromatography on Sepharose-cotinine.
  • the affinity purified material was diluted in 0.5 M sodium carbonate, pH 9.5, at a concentration of 350 ⁇ g/ml.
  • Rabbit anti-sheep antibody (Jackson Immunoresearch Labs) was diluted to 1.2 mg/ml in 0.5 M sodium carbonate, pH 9.3.
  • Nylon membranes Biodyne A, 5 ⁇ m pore size, Pall Biomembranes, NY
  • Affinity purified rabbit anticotinine antibody and the control antibody were applied to the sheet of nylon as lines (20 ⁇ l per line, 8 cm long at the rate of 2.5 ⁇ l/cm).
  • the line widths were 2 cm and 2.5 cm, respectively, from the bottom end of the sheet, parallel to the 10 cm side.
  • the application was performed using a mechanized air-brush applicacor with 1 ⁇ 7-5 ⁇ 2 bar (25-75 psi) nitrogen.
  • the sheets were then allowed to air dry at room temperature for 1 h followed by 30 minutes in an incubator at 37°C.
  • the sheets were then soaked, with agitation, in an aqueous solution of 0.5% casein, 5% sucrose, 0.1% TRITON X-100, 0.05 M Tris, 0.003 M MgCl 2 , 0.9% NaCl, 0.02% NaN 3 , pH 8.0, for 30 minutes.
  • the sheets were air dried for at least 4 h at room temperature.
  • Blue latex coated with cotinine-BGG diluted to 0.25% in 20% sucrose was applied to the sheet of nylon as zones adjacent and parallel to the affinity purified rabbit anti-cotinine line. Each zone was approximately 0.3 x 0.5 cm with approximately a 1.5 mm gap between each zone. The gaps were visible. The zone was applied about 1.5 cm from the bottom end of the sheet. The application was performed using a mechanized air-brush applicator with 1 ⁇ 7-5 ⁇ 2 bar (25-75 psi) nitrogen. The sheets were then allowed to air dry at room temperature.
  • the 7 x 10 cm sheet was cut into strips 0.5 x 7 cm with each strip having a visible blue latex zone and an affinity purified anti-cotinine line and a control antibody zone.
  • test kit Assay for Cotinine.
  • the test kit was prepared for use by cutting the device at the bottom where indicated by the two marker lines. This exposed the end of the test-strip membrane.
  • the device was put into a sample such that the cut end of the device was in contact with the sample.
  • the device was left to stand in the sample for 10 minutes, after which time the results were read.
  • Samples were urine samples containing known amounts of cotinine.
  • Table 2 summarized the results of Table 1.
  • the number of samples that registered as positive for cotinine under the CDC criteria and using the device are in the "+,+” square (32); the number of samples that registered positive using the device of the invention, but that were negative according to the CDC criteria are shown in the "+,-” square (0); the number of samples that registered as negative using the device, but that are positive according to the CDC criteria are in the "-,+” square (11); and the number of samples that registered negative using the device and that are negative according to the CDC criteria are shown in the "-,-” square.
  • SUMMARY OF COTININE ASSAY RESULTS Result cut-off + 100ng/ml cotinine - Device + 32 0 - 11 17
  • the following observations about accuracy (the percentage of correct assay results using the device), sensitivity (the percentage of correct positive results using the device) and specificity (the percentage of correct negative results using the device) are available from the data in Table 2.
  • the overall accuracy of the assay using the device of the invention to test samples of known cotinine concentration, in which the cut-off for a positive result is 100 ng/ml, is 81.6% (49 out of 60). This value is calculated by adding all of the "+,+" and "-,-” values and dividing by the total number of tests.
  • the sensitivity of the assay using the device which is calculated from the number of samples that registered positive divided by the total number of positive samples according to the CDC criteria, was 74.4% (32 out of 43).
  • the specificity of the device which is calculated from the number of samples that registered negative divided by the total number of negative samples according to the CDC criteria, was 100% (17/17).

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
EP94914781A 1993-04-13 1994-04-13 An integrated packaging-holder device for immunochromatographic assays in flow-through or dipstick formats Expired - Lifetime EP0694167B1 (en)

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US08/047,156 US5500375A (en) 1993-04-13 1993-04-13 Integrated packaging-holder device for immunochromatographic assays in flow-through or dipstick formats
US47156 1993-04-13
PCT/US1994/004072 WO1994024563A1 (en) 1993-04-13 1994-04-13 An integrated packaging-holder device for immunochromatographic assays in flow-through or dipstick formats

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EP0694167A1 EP0694167A1 (en) 1996-01-31
EP0694167B1 true EP0694167B1 (en) 2001-08-16

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EP (1) EP0694167B1 (da)
JP (3) JPH08509291A (da)
AT (1) ATE204383T1 (da)
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DE (1) DE69427969T2 (da)
DK (1) DK0694167T3 (da)
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Also Published As

Publication number Publication date
DK0694167T3 (da) 2001-12-10
JP2003232792A (ja) 2003-08-22
JPH08509291A (ja) 1996-10-01
PT694167E (pt) 2002-02-28
CA2160160C (en) 2002-02-12
JP3818967B2 (ja) 2006-09-06
US5500375A (en) 1996-03-19
DE69427969T2 (de) 2002-04-11
WO1994024563A1 (en) 1994-10-27
CA2160160A1 (en) 1994-10-27
JP2006091023A (ja) 2006-04-06
AU6704194A (en) 1994-11-08
US6087185A (en) 2000-07-11
ATE204383T1 (de) 2001-09-15
AU689774B2 (en) 1998-04-09
EP0694167A1 (en) 1996-01-31
DE69427969D1 (de) 2001-09-20
ES2163438T3 (es) 2002-02-01

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